Lookup NU author(s): Dr Mariana Rocha,
Dr John Grady,
Dr Langping He,
Professor Bobby McFarland,
Dr Yi Ng,
Dr Grainne Gorman,
Dr Andrew Schaefer,
Dr Helen Tuppen,
Professor Robert Taylor,
Emeritus Professor Doug Turnbull
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 American Neurological Association Objective: Single, large-scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large-scale mtDNA deletions in skeletal muscle. Methods: We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large-scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction. Results: We have defined 3 “classes” of single, large-scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class. Interpretation: Combining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex-specific protein-encoding genes. Furthermore, removal of mt-tRNA genes impacts specific complexes only at high deletion levels, when complex-specific protein-encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130.
Author(s): Rocha MC, Rosa HS, Grady JP, Blakely EL, He L, Romain N, Haller RG, Newman J, McFarland R, Ng YS, Gorman GS, Schaefer AM, Tuppen HA, Taylor RW, Turnbull DM
Publication type: Article
Publication status: Published
Journal: Annals of Neurology
Online publication date: 24/01/2018
Acceptance date: 21/12/2017
Date deposited: 19/04/2018
ISSN (print): 0364-5134
ISSN (electronic): 1531-8249
Publisher: John Wiley and Sons Inc.
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